Circulating thrombomodulin and hematological alterations in type 2 diabetic patients with retinopathy

To clarify the relationship between circulating thrombomodulin (TM) and endothelial cell damage in diabetes mellitus, plasma levels of TM were quantitated by an enzyme linked immunoabsorbant assay (ELISA) in 164 type 2 diabetes mellitus and 72 normal control subjects, and these levels were compared with those of von Willebrand factor antigen (vWf: Ag), thrombin antithrombin III complexes (TAT), plasmin-alpha2-plasmin inhibitor complexes (PIC), fibrinogen, D-dimer, urinary albumin excretion rate (AER), intima-media thickness (IMT) and plaque score of the common carotid artery assessed with high resolution B-mode ultrasonography. Plasma levels of TM, vWf: Ag, TAT, PIC, AER, IMT and plaque score were significantly increased in the diabetic patients compared to the normal control subjects. Plasma TM levels showed significant correlation with vWf: Ag (r=0.350, p<0.0001), TAT (r = 0.334, p < 0.0001), PIC (r = 0.450, p < 0.0001), AER (r = 0.334, p < 0.0001), IMT (r = 0.181, P<0.01), plaque score (r=0.385, p<0.0001). Among four groups of diabetic patients, divided based on their severity of diabetic retinopathy, there were no significant differences in age, sex, systolic and diastolic blood pressure levels, HbA,1c, or plasma lipid levels, although the plasma levels of TM, vWf: Ag, TAT, PIC, AER, IMT and the plaque score in the patients with proliferative retinopathy were significantly higher than those of the healthy controls and patients with simple retinopathy. Among the 43 normoalbuminuric patients without intima-media thickness or thickened plaque (AER<30 mg/g Creatinine, IMT<1.0 mm, plaque score = 0), plasma levels of TM, vWf: Ag, TAT, PIC were significantly higher in those patients with retinopathy than in those without retinopathy. Multivariate analysis showed TM, TAT and PIC levels to be independent predictors of diabetic retinopathy. In conclusion, circulating TM reflects endothelial cell damage in patients with diabetic retinopathy, and hypercoagulability might play an important role in endothelial cell damage.     

Possible effect of secretor locus on plasma concentration of factor VIII and von Willebrand factor

A significant fraction (30%) of the genetically determined variance in plasma concentration of the von Willebrand factor antigen (vWf:Ag) has been shown to be related to ABH determinants. Individuals with blood group O, who have the highest amounts of blood group H substance, have the lowest concentration of vWf:Ag. The Lewis substances, Le(a) and Le(b), are biochemically closely related to the ABH substances as both can be produced from the same precursor substance. We studied the effect of the presence of the Lewis antigens on the plasma concentration of vWf:Ag and factor VIII antigen (VIII:Ag) in 323 individuals of different ABO groups from a series of twins and in 58 blood donors of blood group O. Among persons belonging to blood group O, those with the Le(a) antigen had a higher concentration of both vWf:Ag and VIII:Ag than individuals lacking Le(a). Le(a+b-) people are nonsecretors and Le(a-b+) people are secretors of ABH substance. Thus, the lowest concentration of vWf:Ag and VIII:Ag was found in group O secretors. The effect is most likely due to an effect of the secretor locus. This finding may be of importance for the detection of carriers of hemophilia A and for the diagnosis of type I von Willebrand disease.     

Diabetes-like alterations in hemostatic parameters after growth hormone administration for one week in normal man

Excess production of growth hormone (GH) in poorly controlled diabetes is believed to be a causal factor in the development of diabetic anglopathy, the mechanism(s) of which is unknown. The present study was undertaken to determine whether exogenous growth hormone would specifically change some quantities and functional parameters known to often be abnormal in long-standing diabetes and thought to result from the development of vascular lesions in general. The authors studied capillary resistance, factor VIII coagulant antigen (F VIII:Ag), von Willebrand factor (vWf:Ag), fibronectin, fibrinogen, and tissue-type plasminogen activator (t-PA) before, during, and after 1 week's subcutaneous GH administration (6 IU per day divided into two doses). Capillary resistance decreased insignificantly, but returned to higher levels (p < 0.05) 1 week after withdrawal. F VIII:Ag, vWf:Ag, fibronectin, and fibrinogen all increased significantly during GH treatment. Except for F VIII:Ag, these quantities returned to premedication levels 7 days after termination of GH administration. The present results may contribute to the clarification of the role of GH hypersecretion in diabetic microangiopathy and macroangiopathy.     

Comparison of the in vitro characteristics of von Willebrand factor in British and commercial factor VIII concentrates

Qualitative/quantitative analysis of von Willebrand factor antigen (vWf:Ag) in either heat or solvent/detergent treated factor VIII concentrates, used for haemophilia replacement therapy, was undertaken to assess their suitability for the treatment of vWD. For the first time immunoaffinity purified vWf:Ag (Monoclate by-product) was also evaluated by in vitro assessment. Potencies of vWf:Ag varied considerably but were consistently higher (28.9-420.5 iu/ml) than factor VIII:C (one-stage) activity (8.13-42.44 iu/ml). The functional activity of vWf was assessed by either Ristocetin Cofactor (vWf:RCo) or collagen binding methods (vWf:CBA) with typical vWf:RCo/vWf:Ag ratios ranging from 0.08 to 0.94. Multimeric analysis confirmed that in vitro biological activity was dependent on the presence of the high molecular weight forms of vWf:Ag. A significant correlation (r = 0.95) between vWf:RCo activity and collagen binding was observed in all of the concentrates with the exception of the immunopurified product. The data suggest that either NHS 8Y (mean vWfRCo/vWf:Ag = 0.94), Haemate P (mean vWf:RCo/vWf:Ag = 0.69) and high purity Octapharma V.I (vWf:RCo/vWf:Ag = 0.82) which contain medium/high MW vWf:Ag multimers are likely to be most cost-effective in the treatment of symptomatic severe vWD patients than other currently available concentrates.     

Haemostatic Measures in Type 2 Diabetic Patients with Microalbuminuria

The major cause of disability and early mortality in Type 2 diabetes is cardiovascular disease. An enhanced urinary albumin excretion is strongly predictive of increased mortality, but the causal relationship behind this association is unclear. Abnormalities in the haemostatic system may be involved in the vascular pathology. We therefore studied the level of von Willebrand factor (vWf:Ag), factor VIII (VIII:Ag), fibrinogen, and fibronectin in male diabetic patients 50–70 years of age, with normal albumin excretion (n = 14), microalbuminuria (n = 14), and frank albuminuria (n = 7). Fourteen healthy age-matched males served as a reference group. There were no significant differences between normo-and micro-albuminuric patients but vWf:Ag (p < 0.01), VIII:Ag (p < 0.01), and fibrinogen (p < 0.05) were increased in those with frank albuminuria. Urinary albumin excretion rate was significantly correlated to vWf:Ag (r = 0.46, p = 0.005), VIII:Ag (r = 0.45, p = 0.007), and fibrinogen (r = 0.49, p = 0.003). The known duration of diabetes was correlated to vWf and F VIII. The increased level of vWf:Ag in Type 2 diabetes and the significant association to the urinary albumin excretion rate may suggest a linkage between albuminuria and cardiovascular disease. However, the present study demonstrated no increase in haemostatic variables in patients with microalbuminuria as compared with those with normal albumin excretion.     

Increased factor VIII/vWf levels in patients with reduced platelet number

Summary Factor VIII/von Willebrand factor (VIII/vWf) related properties were studied in twenty six patients with thrombocytopenia. Fifteen patients were affected by idiophatic thrombocytopenic purpura (ITP) and 11 patients by thrombocytopenia of a different nature or non-ITP (n-ITP). All patients showed an enhancement of platelet associated IgG (PAIgG). A significant increase of factor VIII ristocetin cofactor (VIII R: RCoF) and factor VIII related antigen (VIII R: Ag) was found in ITP patients while normal values were observed for factor VIII coagulant (VIII: C). All factor VIII/vWf components, on the contrary, were increased in n-ITP group with a prevalence of VIII R: RCoF as observed in ITP group even though with lower mean values. Multimeric analysis of VIII/vWf demonstrated a higher concentration of all multimeric components, with major representation of higher molecular weight multimers (HMWM) in patients of both groups.Two patients were studied before and after improvement in platelet count. A decrease of vWf related properties (VIII R : RCoF and VIII R : Ag) concomitant with the increase in platelet count was found. In n-ITP patients a statistical correlation between VIII R : RCoF and PAIgG was also observed while no correlation was found between other factor VIII/vWf components and PAIgG both in ITP and n-ITP patients.     

Discrepant increase in factor VIII: C and von Willebrand factor after DDAVP infusion in a patient with variant von Willebrand's disease.

We have studied a patient with von Willebrand's disease (vWd) whose von Willebrand factor (vWf) multimer patterns showed significant decreases of all but the major fast moving vWf multimer (promoter). Bleeding time (BT) was very prolonged, there was almost no ristocetin-induced platelet aggregation (RIPA) and vWf levels were very low. The factor VIII: C/vWf: Ag ratio appeared to be higher than normal because of the relatively increased concentration of factor VIII: C. The infusion of DDAVP normalized BT, improved RIPA and restored normal factor VIII: C levels, these effects lasted for 5 h even though only a slight increase of vWf: Ag and vWf: RCoF was observed. RIPA was completely inhibited by an anti-glycoprotein (GP) Ib monoclonal antibody that recognizes the ristocetin-induced vWf binding site. Plasma vWf multimer analysis revealed only slight increases of all components and an additional, more pronounced representation of vWf protomer. These data suggest that the patient has an abnormal vWf molecule characterized by a greater ability to carry factor VIII than would be expected from the vWf levels. Furthermore, since the vWf protomer was the only significant vWf component present both before and after DDAVP infusion we hypothesize that some of the haemostatic functions of the patient's vWf may depend on it.     

Regulation of coagulo-fibrinolytic activity and lupus anticoagulants in systemic lupus erythematosus

We determined the following coagulo-fibrinolytic activities in 24 patients with systemic lupus erythematosus (SLE) and 20 healthy adults: prothrombin time (PT), activated partial thromboplastin time (A-PTT), factor VIII: coagulant activity), von Willebrand factor antigen (vWF: Ag), antithrombin-III (AT-III), plasminogen (PLG), alpha 2 plasmin inhibitor (alpha 2 PI), alpha 2-plasmin inhibitor-plasmin complex (PIC), protein C (PC: activity and antigen concentration), and protein S (PS: total PS and free PS). PLG, AT-III, PC antigen concentration and total PS were significantly decreased in ten female controls as compared with ten male controls. Therefore, we used the ten healthy females as controls and excluded two male SLE patients in the analysis of the correlations of coagulo-fibrinolytic activities with lupus anticoagulant (LA), clinical and laboratory features in 22 female patients with SLE. In the SLE patients, PT was significantly shortened, while A-PTT was prolonged. PLG, PC activity and antigen, and total PS were significantly increased, and free PS levels were decreased in SLE. The shortened PT and decreased free PS suggest hypercoagulable states in SLE patients. A significant prolongation of A-PTT and a decrease of F VIII activity were observed in the six LA-positive SLE patients, and the results were considered as known effects of LA. Furthermore, vWF: Ag, AT-III and PC antigen levels were significantly increased in the LA-positive patients as compared with LA-negative patients. These changes indicate both vascular endothelial cell damages and a compensatory increase in coagulation inhibitors in the LA-positive patients.     

Coagulation studies in thrombotic thrombocytopenic purpura, with special reference to von Willebrand factor and protein S

The profile of blood coagulation and fibrinolysis was studied in detail in eight patients with acute thrombotic thrombocytopenic purpura (TTP). In the majority of the patients, fibrinogen, factor XIII, antithrombin III, alpha 2-plasmin inhibitor, plasminogen, and alpha 2-macroglobulin were normal, whereas FDP, plasmin-alpha 2-plasmin inhibitor complex, and tissue-type plasminogen activator antigen were marginally or moderately elevated. Low fibronectin values were observed in four patients. Protein C and C4b-binding protein were nearly normal, whereas total protein S and free protein S were reduced in five and six patients, respectively. A positive correlation was found between total protein S and C4 and between free protein S and C3. von Willebrand factor antigen (vWf:Ag) and ristocetin cofactor (RCof) were either normal or elevated, but RCof/vWf:Ag ratio was decreased in seven patients. Crossed immunoelectrophoresis and sodium dodecyl sulfate (SDS)-agarose gel electrophoresis revealed that the large vWf multimers were either absent from or relatively decreased in all patients except one. In addition, one patient had unusually large vWf multimers, and a low-molecular-weight vWf fragment was apparently observed in three patients. These findings indicate that the intravascular generation of thrombin and plasmin was minimal in TTP and suggest that the alterations of the vWf molecule were caused not only by consumption through its participation in platelet thrombus formation but also by accelerated proteolysis. Low protein S values would be related to the immunological abnormalities underlying TTP.     

Changes induced by venous occlusion in coagulation and fibrinolysis in patients with old myocardial infarction

The levels of hemostatic and fibrinolytic parameters and of molecular markers in venous blood before and after 10 minutes of venous occlusion were measured to evaluate vascular endothelial function in 36 patients with old myocardial infarction, and also in 20 healthy subjects. T-PA activity in the venous blood after occlusion was significantly lower in the patient group compared with the control group, and was lowest in patients with diabetes mellitus. These results were considered to be attributable to elevated PAI-1 and alpha 2 PI levels in these patients. The mean levels of t-PA antigen and VIII R: Ag in venous blood before occlusion were significantly higher in the patient group, but the mean amount of release was no higher in patients than in controls. The plasmin.alpha 2PI complex levels before venous occlusion seemed to indicate the presence of secondary fibrinolysis accompanying hypercoagulability, and the level was significantly higher in patients with diabetes mellitus. Venous occlusion induced the release of t-PA and VIII R: Ag without causing a significant difference in the mean amount of increase of these substances in patient and control groups. However, the lower level of t-PA activity after venous occlusion together with the higher levels of VIII: C, VIII R: Ag, alpha 2PI, PAI-1, and plasmin.alpha 2PI complex before venous occlusion in the patients, indicated that the patient group was in a hypercoagulable and hypofibrinolytic state. In those with diabetes mellitus, the changes were more significant.     

A prospective study of G-CSF effects on hemostasis in allogeneic blood stem cell donors.

Granulocyte colony-stimulating factor (G-CSF) is used in healthy donors of peripheral blood stem cells (PBSC) for allogeneic transplantation. However, some data have recently suggested that G-CSF may induce a hypercoagulable state, prompting us to study prospectively 22 PBSC donors before and after G-CSF 5 microg/kg twice daily. We sought evidence for changes in the following parameters: platelet count, von Willebrand factor antigen (vWF:Ag) and activity (vWF activity), beta-thromboglobulin (beta-TG), platelet factor 4 (PF-4), platelet activation markers (GMP-140 and PAC-1), activated partial thromboplastin time (aPTT), prothrombin time (PT), coagulant factor VIII (FVIII:C), thrombin-antithrombin complex (TAT), prothrombin fragment 1+2 (F1+2), thrombomodulin (TM) and tissue plasminogen activator antigen (tPA:Ag) prior to G-CSF and immediately before leukapheresis. ADP-induced platelet aggregation studies were also performed. G-CSF administration produced only mild discomfort. We found a significant increase in vWF:Ag (from 0.99 +/- 0.32 U/ml to 1.83 +/- 0.69 U/ml; P < 0.001), in vWF activity (from 1.04 +/- 0.34 U/ml to 1.78 +/- 0.50 U/ml; P < 0.001) and in FVIII:C (from 1.12 +/- 0.37 U/ml to 1.73 +/- 0.57 U/ml; P < 0.001) after G-CSF. Of note, four donors with low baseline vWF had a two- to three-fold increase after receiving G-CSF. G-CSF had no impact on the platelet count, beta-TG, PF-4, GMP-140 or PAC-1. The final% of platelet aggregation decreased from 73 +/- 22% to 37 +/- 26% after G-CSF (P < 0.001). We found a significant decrease in aPTT after G-CSF (29.9 +/- 3.1 s to 28.3 +/- 3.3 s; P = 0.004), but the PT was unaffected. In addition, we also observed a significant increase in TAT, F1+2 and TM, but not in tPA:Ag. Our data suggest that G-CSF may possibly induce a hypercoagulable state by increasing levels of FVIII:C and thrombin generation. In contrast to this information, we found reduced platelet aggregation after G-CSF administration. The clinical implications of these findings remain unclear and larger studies are definitely required.     

IgA inhibitor to factor VIII/von Willebrand factor

A 60-year-old Black female presented with a haemorrhagic diathesis and an acquired factor VIII/von Willebrand factor (VIII/vWf) inhibitor. This inhibitor was classified as an IgA immunoglobulin and was active not only against factor VIII coagulant (VIII:C) activity but also against plasma von Willebrand factor (vWf). The purified IgA also interacted with normal platelets to inhibit ristocetin-induced platelet aggregation (RIPA). In contrast, studies with haemophilia A plasma and platelets revealed that the inhibitor did not react significantly with these plasmas or platelets. The significant differences in the inhibition of vWf assay both of the plasma and the platelets of the haemophilia A patients suggests that part of the haemorrhagic diathesis may be related not only to the inhibition of VIII:C but also to interference with platelet function. In addition, these studies suggest that there may be significant differences in the factor VIII-related antigen (VIII R:Ag) on platelets in haemophilia A patients compared to normal.     

The Release of Plasminogen Activator and Factor VIII after Injection of DDAVP in Healthy Volunteers and in Patients with von Willebrand's Disease

Increases in plasma concentrations of VIII:C, VIII:CAg, VIIIR:Ag and plasminogen activator (PA) were observed in 50 healthy volunteers given i.v. injections of DDAVP (desaminocys¹-8-D-arg-vasopressin). The PA activity reached its maximum immediately after the injection, VIII:C, VIII:CAg and VIIIR:Ag after 3040 min. However, a positive correlation was found when the PA and VIII:C responses in each of the normals were analysed. DDAVP was also administered to 3 patients with severe von Willebrand's disease. 2 of the patients displayed no changes in VIII:C, VIII:CAg, VIIIR:Ag or VIIIR:RCF and there was no increase in PA. The third patient responded with an increase in VIII:C and to a minor degree in VIII:CAg. This patient developed fibrinolytic activity, but in the lower normal range. In 3 other patients with mild von Willebrand's disease DDAVP caused increases in VIII:C, VIII:CAg, VIIIR:Ag and PA. We feel that the combined data may support the concept that one and the same target cell is involved in the DDAVP mediated release of factor VIII related activities and PA.     

Procoagulant Specificity of Factor VIII Inhibitor

Nine haemophilia A patients with an inhibitor to factor VIII procoagulant and eight without an inhibitor were studied for the presence of an inhibitor to von Willebrand factor (vWf) in a quantitative ristocetin-induced platelet aggregation system. The mean vWf, factor VIII related antigen (FVIII Ag) and vWf:FVIII Ag ratio were not significantly different in the two groups (P greater than 0.6). The inhibitor plasmas did not reduce the wWf level in normal plasma after a 2 h incubation. The factor VIII inhibitor is highly specific for the procoagulant function of the factor VIII complex.     

Hemostatic abnormalities in cirrhosis and tumor-related portal vein thrombosis

In order to investigate the relationship between hemostatic abnormalities and portal vein thrombosis (PVT) in hepatocellular carcinoma (HCC), platelets, prothrombin time (PT), activated partial thromboplastin time (aPTT), thrombin time, fibrinogen, d-dimer, fibrinogen degradation products (FDPs), protein C, protein S, antithrombin, plasminogen, antiplasmin, coagulation factors (CFs) V, VII, VIII, IX, XI, and XIII, von Willebrand factor (vWF), prothrombin fragment 1 + 2 (PF 1 + 2), tissue-type plasminogen activator (tPA), and plasminogen activator inhibitor 1 (PAI-1) were studied in patients with HCC, cholangiocarcinoma, and metastatic liver tumors and in cirrhosis patients with or without PVT. Platelet, antithrombin, protein C, plasminogen, and CFs V, VII, IX, XI, and XIII levels of HCC group were found lower and PT, aPTT, thrombin time, vWF, FDPs, PF 1 + 2, tPA, and PAI-1 levels were higher than the control group. Our findings suggested that the abnormalities of coagulation and fibrinolysis systems have some role in provoking thrombosis of portal veins in HCC, in addition to the invasion of portal veins by hepatoma cells.     

Clinical and laboratory evaluation of National Health Service factor VIII concentrate (8Y) for the treatment of von Willebrand''s disease

This study was carried out to assess the efficacy of NHS 8Y concentrate in the treatment of patients with von Willebrand's disease (vWD). Eight patients (two type I vWD, one type IIA vWD, two type IIB vWD, and three type III vWD) were treated on a total of 10 occasions with 8Y. Following each treatment episode there was a temporary correction of patients' bleeding time (BT) measurements. Other laboratory parameters--von Willebrand factor ristocetin cofactor activity (vWf:RiCo), vWf antigen (vWf:Ag) levels, and factor VIII coagulant activity (factor VIII:C)--were also corrected. Plasma vWf multimers temporarily reflected those present in the infused concentrate. An effective clinical response was observed in each case despite, as revealed by autoradiography and scanning densitometry of SDS-agarose electrophoresis gels, a reduction in the concentration of the largest vWf multimers in 8Y compared with normal plasma. Overall, the clinical effectiveness of 8Y in vWD was comparable to that seen with cryoprecipitate. We conclude that NHS 8Y concentrate may be used as an alternative to cryoprecipitate for the treatment of vWD.     

Further evidence that the residual vWf:Ag in porcine FVIII:C induces human platelet aggregation

Porcine or bovine factor VIII concentrates (FVIII:C) have been used during the past 3 decades to control bleeding in patients who have developed antibodies to human factor VIII. Since current preparations of animal FVIII:C are not known to transmit infectious agents such as hepatitis or human immunodeficiency virus, they are of potential therapeutic interest. A purified porcine FVIII:C (Hyate:C) is now widely used as an alternative to human FVIII:C in patients with inhibitor. Unlike earlier preparations of porcine FVIII:C, thrombocytopaenia is rare with the current preparation. Nonetheless, it causes the aggregation of human platelets in vitro. Our aim was to identify precisely the plasma factor which induces platelet aggregation. The effects of commercial porcine FVIII:C, porcine fibrinogen, porcine fibronectin and the corresponding preparations from human origin on platelet aggregation were studied. Platelet aggregation was quantified by measuring the fall in single platelet count in human whole blood. Of these preparations, only porcine FVIII:C (0.1-1 U/ml) and porcine fibrinogen (80-600 micrograms/ml) induced a fall in single platelet count of up to 85% due to aggregation. The extent of aggregation was directly proportional to the amount (0.007-0.1 U/ml test aliquot) of residual von Willebrand factor antigen (vWf:Ag) in the preparations. A monoclonal antibody to vWf:Ag inhibited the aggregation. We believe that the aggregation of human platelets induced in vitro by porcine FVIII:C is mediated by vWf:Ag which also may be responsible for thrombocytopaenia reported following administration of porcine FVIII:C in vivo.     

Hyper-responsiveness to DDAVP for patients with type I von Willebrand's disease and normal intra-platelet von Willebrand factor

Desmopressin (DDAVP) has gained wide acceptance as the drug of first choice in the treatment or prevention of haemorrhages in the majority of patients with von Willebrand's disease (vWd). However, data concerning the clinical effectiveness of DDAVP refer generally to mild vWd, with factor VIII and vW factor levels usually above 20% of normal. In 14 patients with type I vWd characterized by very low plasma levels of factor VIII coagulant activity (VIII:C) and vWf, measured as ristocetin cofactor activity (lower than 20% and 3% of normal respectively), but with a normal intraplatelet content of vWf, a test infusion of DDAVP (0.4 microgram/kg) elicited a very marked increase of VIII:C and vWf and normalized the bleeding time. All these patients subsequently underwent tooth extraction after DDAVP infusion. The incidence of bleeding was remarkably low, with only two minor late bleeding episodes easily stopped by repeating DDAVP infusion. Compared to the cases of type I vWd with unknown intraplatelet vWf content reported in the literature, this subgroup of patients had a more marked, albeit short-lived, increment of VIII:C and vWf.     

Acquired von Willebrand's disease in association with Wilm's tumor: regression following treatment

A 9-yr-old female presented with a Wilm's tumor and a coagulopathy consistent with von Willebrand's disease. Factor VIII procoagulant activity (VIII C), factor VIII related antigen (VIIIR:Ag), and von Willebrand factor activity (VIII:vWf) were decreased. There was no evidence for a circulating inhibitor of the factor VIII molecular complex. von Willebrand's antigen II (vW AgII), which is deficient in hereditary von Willebrand's disease, was decreased below detectable levels in this patient. The coagulation studies, VIIIR:Ag, and vW AgII levels returned to normal following therapy of the Wilm's tumor. Wilm's tumor must be included as one of the malignancies associated with acquired von Willebrand's disease. Immunofluorescent studies of the tumor specimen showed normal endothelial staining of VIIIR:Ag by semiquantitative techniques and a lack of specific tumor adsorption of VIIIR:Ag The presence of normal amounts of tissue VIIIR:Ag has not previously been demonstrated in acquired von Willebrand's disease. Since we failed to demonstrate an inhibitor in the plasma in this patient, the etiology of the acquired von Willebrand's disease in this patient appears to differ from other cases of acquired von Willebrand's disease. The finding that vW AgII is decreased in this patient, similar to that reported in hereditary von Willebrand's disease, supports the close association of vW AgII to VIIIR:Ag, even though they are immunologically and biochemically distinct.     

Effectiveness, specificity and safety of intranasal 1-deamino-8-D-arginine vasopressin treatment of normal blood donors

A study of the absorption of 300 micrograms of 1-deamino-8-D-arginine vasopressin (DDAVP) given intranasally to normal blood donors was carried out to determine (a) the correlation between plasma levels of DDAVP and the percent rise of factor VIII procoagulant activity (VIII:C) and (b) the efficacy, specificity and safety of this treatment in increasing the recovery of factor VIII:C in donated blood. The maximum drug concentration was highly correlated to the maximum percent rise of VIII:C (r = 0.858, p less than 0.01). A differentiated effect of DDAVP on increases of VIII:C, VIII:Ag, vWF:Ag and vWF multimers was observed. A transient rise of fibrinopeptide A from 5 to 16 ng/ml, 30 min post-DDAVP, was not accompanied by changes in fibrinogen levels or generation of detectable factor Xa or thrombin. DDAVP had no effect on the factor XII-dependent pathway of plasminogen activation, or on the donor's vital signs and hematological parameters. Side effects were minor and of short duration. Intranasal DDAVP treatment of blood donors is considered to be a practical means of improving the recovery of VIII:C from normal donors.